Oxygen plays a critical biological role as the terminal electron acceptor in the mitochondria of vertebrate cells. During evolution, these cells have developed ways to sense alterations in oxygen levels and, during this process, acquired the ability to conditionally modulate the expression of genes involved in adaptive physiological responses to hypoxia including angiogenesis, erythropoiesis, and glycolysis. These genes include vascular endothelial growth factor, eryhtropoietin, several glycolytic enzymes and inducible nitric oxide synthase, and have all been shown to contain hypoxia responsive elements (HREs) (for reviews, see Guillemin and Krasnow (1997) Cell 89, 9–12; Wenger and Gassmann (1997) Biol. Chem. 378, 609–616). Under hypoxic conditions these response elements are recognized by a heterodimeric complex consisting of the hypoxia inducible factor-1α (HIF-1α) and Arnt (Wang et al. (1995) Proc. Natl. Acad. Sci. USA 92, 5510–5514; Gradin et al. (1996) Mol. Cell. Biol. 16, 5221–5231). Both these transcription factors belong to the rapidly growing family of basic-helix-loop-helix (bHLH)-PAS (Per, Arnt, Sim) proteins.
A family of helix-loop-helix proteins designated Id18 has been identified as antagonists of bHLH transcriptional regulators. bHLH proteins typically bind regulatory sequences in a heterodimeric configuration and function to activate differentiation-linked gene expression. The heterodimer usually comprises a class A bHLH protein together with a class B bHLH protein. In the presence of excess Id protein, the class A bHLH partner is typically titrated out through heterodimerization with Id protein.
Dysregulation or overfunction of HIF-1α might cause a variety of pathological conditions including tumor progression15 16 7 and inflammatory angiogenesis17. Consequently, there is a need for identification of compounds acting as negative regulators of HIF-1α, said compounds being potentially useful against medical conditions related to angiogenesis and tumor progression.